There are several pathological conditions that involve irregularities in calcium metabolism. Such are some bone related diseases as Paget's disease, osteoporosis as well as osteolysis in bone metastases.
Bone metastases present a major problem in many frequently occurring malignancies. Hypercalcemia, resulting from bone resorption, is a common and very important complication of malignancy, causing most distressful symptoms, such as severe pain, spontaneous fractures, and may lead to a metabolic coma and death. Moreover, neoplastic cell-induced osteolysis may determine the localization and growth enhancement of the tumor. (G. R. Mundy, Bone, 8, supp. 1, S9-5 16 (1987); Calcium in Biological Systems, R. P. Rubin, G. B. Weiss, and J. W. Putney, Jr. eds. Plenum Press, New York (1985)). Ectopic calcification is a seemingly opposite type of pathological condition, characterized by the deposition for calcium phosphate in a number of clinically important diseases as, for example, atherosclerosis, kidney and renal calculus, arthritis, and bioprostetic heart valve calcification, and implanted biomaterial calcification such as bioprostetic and prosthetic heart valves, vascular grafts, LVAD (left ventricular assist devices), contact lenses and a total artificial heart.
Bisphosphonates are a relatively new class of drugs that have been developed for use in various metabolic diseases of bone, the target being excessive bone resorption and inappropriate calcification and ossification. (M. D. Francis and R. R. Martodam, in "The Role of Phosphonates in Living Systems" R. L. Hilderbrand, ed. CRC Press, Boca Raton, Fla., 1983, pp. 55-96; H. Fleisch, Bone, 1987, 8, Supp. 1, S23-S28). Recently there have been reports of encouraging clinical trials utilizing bisphosphonates to treat hypercalcemia in patients with breast cancer, myeloma, and bronchial carcinoma related osteolytic metastases, in addition to the established usage of bisphosphonates in Paget's disease and for diagnostic purposes in bone mapping. However, bisphosphonate therapy is frequently accompanied by severe side effects. Bisphosphonates have been also found highly potent both in inhibiting bioprosthetic heart valve calcification, and in experimental arteriosclerosis, however, this was accompanied by severe adverse effects on bone development and overall somatic growth.
The currently used bisphosphonates all belong to the geminal type, in which the two phosphoryl groups are bound to the same carbon ("P--C--P"), and therefore may be viewed as pyrophosphate analogs in which the oxygen between the two phosphorus atoms is replaced by a carbon.
In contrast, monophosphonates, vicinal bisphosphonates (P--C--C--P) and compounds in which the distance between the phosphoryl group is longer (P--(C).sub.n --P, n&gt;2) are reported to be less active or inactive at all.
From the results obtained in various clinical studies using conventional bisphosphonates it appears that there is a need for compounds which have greater margin between the bone resorption inhibiting effect and that inhibiting mineralization, without an increase in toxicity.
According to the present invention it was found that introduction of modifications into long chain bisphosphonates of type P--(C).sub.n --P increases the cation binding ability of these compounds, and inhibits ectopic calcification. The advantage in this type of compound in interacting with calcium phosphate crystals is assumed to derive from the presence of an additional independent anchor site(s) in the molecule as compared with known bisphosphonates. An additional advantage of this novel class of compounds is an effect of long duration and the enhanced ability to interact with the cell membrane.
U.S. Pat. No. 3,012,054 from Mar. 18, 1960 and a paper by M. Kanaan and R. Burgada, Phosphorus and Sulfur, 1988, 37, 217-229, describe the preparation of "tetraalkyl esters of diphosphonates" having the structure: ##STR2## wherein R=alkyl radical containing 1-4 carbons and n=2 to 8, inclusive.
It should be emphasized that the patent mentioned deals only with tetraesters. It is well known that such dialkyl acylphosphonates, as mentioned, exhibit extreme instability toward water, and they hydrolyze to the corresponding carboxylic acids both in acidic and alkaline conditions. Consequently, hydrolysis of the tetraalkyl esters described in the patent and the paper cited above would lead to dicarboxylic acids HOOC--(CH.sub.2).sub.n --COOH. Therefore, the syntheses of dealkylated derivatives such as represented by the formulas below: ##STR3## require special nonhydrolytic methods, and by no means are the dealkylated compounds obvious derivatives of the tetraesters.
Neither esters nor acids of bisphosphonates in which the two ketophosphonic groups such as aromatic rings etc., have been reported.